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Yongping Shao

The new melanoma drug, Zelboraf ---Successes and challenges. Yongping Shao. Dr. Andrew Aplin’s Lab Kimmel Cancer Center Thomas Jefferson University. Cutaneous melanoma. Cutaneous melanoma is a type of skin cancer formed by neoplastic melanocytes.

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Yongping Shao

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  1. The new melanoma drug, Zelboraf ---Successes and challenges Yongping Shao Dr. Andrew Aplin’s Lab Kimmel Cancer Center Thomas Jefferson University

  2. Cutaneous melanoma • Cutaneous melanoma is a type of skin cancer formed by neoplastic melanocytes. • Although a less common skin cancer, melanoma is the deadliest and accounts for the majority of skin cancer related death. • Worldwide, doctors diagnose about 160,000 new cases of melanoma each year. • According to a WHO report, about 48,000 melanoma related deaths occur worldwide per year

  3. Melanoma Progression Miller AJ. et al. N Engl J Med, 2006

  4. Cause of Melanoma • Genetic mutations in melanocytes • Tumor suppressor genes: CDKN2A, PTEN etc. • Oncogenes: BRAF, Ras, AKT, PI3K etc. • BRAF gene was found mutated in ~50% of melanoma patients • The most frequent mutation of BRAF is BRAF V600E • UV exposure (Sun, tanning devices) increases the chance of mutation

  5. Melanoma Treatment • For early stages (radial phase): • -surgical excision • For late stages (vertical, metastatic phases) • Radiation • Immunotherapy: IL-2 (Proleukin), lymphocytes CD4+, vaccines, antibodies, • Chemotherapy: Dacarbazine (DTIC) • Targeted therapy: Zelboraf (New FDA approved drug)

  6. Zelboraf (Vemurafenib) An inhibitor of mutant BRAF kinase

  7. Zelboraf How Zelboraf works? Growth factors RTK RTK Melanoma cells Normal melanocytes

  8. Clinical Performance of Zelboraf Baseline Week 15 Week 23 Wagle et al, J Clin Onco, 2011 Flarherty et al, N Engl J Med, 2011 What are the mechanisms of acquired resistance to Zelboraf?

  9. PI3K RTK upregulation (IGF1R, PDGFR etc) AKT Mechanisms of Zelboraf resistance RTK strategy Mechanism PI3K inhibitor +Zelboraf Ras PI3K inhibitor B-Raf C-Raf Zelboraf MEK P ERK P Growth Death Migration

  10. RTK MEK inhibitor +Zelboraf Ras mutation P MEK inhibitor Mechanisms of Zelboraf resistance strategy Mechanism PI3K inhibitor +Zelboraf RTK upregulation (IGF1R, PDGFR etc) Ras B-Raf C-Raf Zelboraf MEK P ERK P Growth Death Migration

  11. RTK PI3K inhibitor +Zelboraf RTK upregulation (IGF1R, PDGFR etc) MEK inhibitor +Zelboraf Ras mutation Cot1 upregulation Cot1 Mechanisms of Zelboraf resistance strategy Mechanism Ras MEK inhibitor +Zelboraf B-Raf C-Raf Zelboraf MEK P MEK inhibitor ERK P Growth Death Migration

  12. RTK PI3K inhibitor +Zelboraf RTK upregulation (IGF1R, PDGFR etc) MEK inhibitor +Zelboraf Ras mutation MEK inhibitor +Zelboraf Cot1 upregulation Zelboraf +ERK inhibitor? MEK mutation ERK inhibitor? Mechanisms of Zelboraf resistance strategy Mechanism Ras B-Raf C-Raf Zelboraf MEK P ERK P Growth Death Migration

  13. Evolving PLX4720 ( a Zelboraf analog) resistant melanoma cells Parental cells (sensitive) Contains BRAFV600E 1-2 weeks + 5μM PLX4720 Persistent cells 2-3 weeks Resistant cells

  14. PLX4720 only partially inhibits ERK signaling in resistant cells P Zelboraf

  15. P Zelboraf MEK inhibitor MEK inhibitor reduces the growth of resistant cells

  16. pro-death Pro-death anti-death anti-death anti-death Pro-death Cell death model Survival Death Survival

  17. Loss of two pro-death proteins, BimEL and Bmf contributes to resistance Zelboraf BimEL Bmf Ras B-Raf C-Raf Bmf BimEL MEK P Parental Resistant Parental Resistant ERK P 16 14 12 DMSO DMSO PLX PLX 10 Relative Bmf mRNA 8 Death BimEL 6 4 2 Actin 0 PLX PLX DMSO DMSO

  18. Re-introduction of “pro-death” proteins kills resistant cells Cell death

  19. HADC inhibitor SAHA induce BimEL and cell death in resistant cells BimEL level Cell death SAHA+PLX

  20. Model Ras B-Raf C-Raf P Zelboraf MEK P MEK inhibitor ERK P ? SAHA Growth Bmf, BimEL Cell death

  21. Acknowledgement • Dr. Andrew Aplin • Dr. Michele Weiss • Dr. Pragati Katiyar • Neda Dadpey • Kaitlyn Le • Ethan Able • Curtis Kugel • Kevin Basile • Halinh Vu • Dr. Gideon Bollag for PLX drug • Outrun the Sun melanoma research scholar award 2010 • NIH grant All the people that support melanoma research!

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